Cerebellar involvement associated with immune checkpoint inhibitors: A systematic review

Immune checkpoint inhibitors (ICIs) targeting programmed death receptor 1 (PD-1), cytotoxic T-lymphocyte-associated-4 (CTLA-4) and programmed cell death ligand 1 can be associated with immune-related adverse events (iRAEs). Amongst neurological iRAEs, cerebellar involvement seems to be rare and currently lacks a proper characterization. The aim of this study was to phenotype cerebellar iRAEs.

A systematic review was performed according to PRISMA guidelines including reported patients with cerebellar involvement related to ICIs and with available individual data.

After screening 2765 records, 32 studies with 46 patients were included. Median age was 63 years (20-82), and most patients were male (63.0%). Isolated cerebellitis was observed in 32.6% of cases, whilst the remaining cases had "cerebellitis plus", mostly associated with encephalitis/encephalopathy. Associated tumors included most frequently lung cancer, melanoma and Merkel cell carcinoma. PD-1 inhibitor was the most administered treatment (n = 29, 64.4%), whilst exposure to CTLA-4 inhibitor was rare (n = 2, 4.5%). Magnetic resonance imaging was abnormal in 43.2% of patients and inflammatory cerebrospinal fluid findings were frequently observed. Autoantibodies were detected in 61.9% of patients and included novel reactivities. Amongst treatment strategies, the most common were steroids (n = 36) and ICI discontinuation (n = 28, 90.3%). Relapses were reported in 10% of patients. Most patients showed improvement/remission (n = 31) but, at last follow-up, 12 had died. Isolated cerebellitis versus cerebellitis-plus differed in terms of outcomes, whilst seropositive versus seronegative patients had distinct tumor associations.

Cerebellar iRAEs are usually multifocal, have heterogeneous tumor associations, are most associated with PD-1 inhibitor exposure and are related to autoantibodies, including novel reactivities.